Our goal is to obtain an accurate understanding of the mechanism of nucleation and oligomerization in polyglutamine aggregation. Our studies will be based on a combination of molecular simulations and fluorescence correlation spectroscopy (PCS) experiments. Polyglutamine aggregation, a nucleation- dependent process, is of direct relevance to the onset and progression of nine different neurological diseases, including Huntington's disease. Details of nucleation mechanisms are relevant for in vivo aggregation given the toxic given the toxic roles ascribed to early intermediates populated on or off the pathways to formation of large aggregates. To adjudicate between the different proposals for nucleation of polyglutamine aggregation, we need detailed simulations of chain oligomerization in systems containing polyglutamine. Toward this end, we developed an efficient and accurate simulation engine, which allows us to simulate conformational and phase equilibria for multiple polyglutamine molecules of varying lengths. This engine named ABSINTH, for Aggregation of Biomolecules Studied using Implicit Novel Tunable Hamiltonians is based on a new method for modeling mean-field interactions of polypeptides with water and water-mediated interactions within and between polypeptides. We can now test specific hypotheses for nucleation and oligomerization of polyglutamine molecules by seeking answers to questions listed below: 1. Does increasing polyglutamine length stabilize intramolecular 3-sheets or reduce the barrier to the formation of these structures? 2. Are unstable, partially swollen conformations characterized by a critical number of (3-sheet contacts better suited than metastable, compact, (3-sheets for nucleation of polyglutamine oligomerization? 3. How do perturbations in overall solvent quality and sequence context influence conformational fluctuations of polyglutamine and how do these fluctuations alter the phase behavior of polyglutamine?